This Project will focus on the development of a robust mouse model in which drugs used clinically in organ transplant patients enhance cutaneous non-melanoma skin carcinogenesis. To develop this model we first will identify combinations of mouse strains, anti-rejection drugs, and ultraviolet radiation in which drugs and UV synergize in enhancing growth of transplanted immunogenic tumor cells. Such synergistic combinations then will be tested in long-term photocarcinogenesis studies to identify combinations in which drugs enhance this process. Since transplant patients nearly always have HPV infections, we also will assess such combinations in K14-HPV16 transgenic mice. Mechanisms by which the drugs enhance carcinogenesis will be assessed first with an integrated and comprehensive series of studies of the effects of these drugs on DNA repair. In addition, the role of drug-induced immunosuppression will be assessed in mice of the standard model which additionally have been made genetically immunodeficient by breeding in of the TCR delta or RAG2 knockout alleles. The effects of rapamycin also will be compared with those of more traditional anti-rejection drugs.